Novel Carboxylic Acid Derivatives

ABSTRACT

The present invention is concerned with novel arylalkyl carboxylic acid derivatives, more specifically, with acylates of arylalkyl carboxylic acids with naturally occurring, non-toxic hydroxy, sulfhydryl, amino or imino compounds, and to compositions containing them. The compositions are preferably cosmetic preparations.

The present invention is concerned with novel arylalkyl carboxylic acidderivatives, more specifically, with acylates of arylalkyl carboxylicacids with naturally occurring, non-toxic hydroxy, sulfhydryl, amino orimino compounds, and to compositions containing them. The compositionsare preferably cosmetic preparations.

More particularly, the invention is concerned with compounds of thegeneral formula

[Ph-(CH₂)_(n)—CO]_(m)—X  (I)

wherein Ph is phenyl or substituted phenyl, n is 1 or 3, m is an integerof at least 1, and X is a moiety from a naturally occurring, non-toxiccompound carrying at least one hydroxyl, sulfhydryl, amino or iminogroup which moiety is formed by removal of a hydrogen atom from saidhydroxyl, sulfhydryl, amino or imino group; except that X is not anamino acid or peptide comprising up to 6 amino acids.

The term ‘naturally occurring, non-toxic hydroxyl, sulfhydryl, amino orimino compounds’ comprises natural occurring compounds such as vitamins,terpenes, chromanes, flavones, catechols, pyrimidines as well assynthetic derivatives or analogues thereof which have been modified inorder to make them susceptible for an attachment to the[Ph-(CH₂)_(n)—CO]_(m) moiety.

It has been found that the compounds provided by the present inventionare particularly useful for treating wrinkles but also for thickeningthe epidermis, repairing the skins lipid barrier, for protection againsthair loss and for improving hair growth.

Human skin undergoes certain normal cornification processes which givethe skin its characteristic appearance. Casual factors or externalfactors such as a raw climate, wind, photo-damage and irritationtriggered by the sun, rain and snow, however, disturb this normalcondition of the skin, and there appears a roughness, a formation ofscales (for example on the scalp), an excessive keratinization andsimilar phenomena. Furthermore, in the course of aging of the skinvarious signs appear that are especially reflected by a change in thestructure and function of the skin. One of these signs is the appearanceof fine lines and deep wrinkles, the size and number of which increaseswith age. The micro relief of the skin becomes less uniform and is ofanisotropic nature. In parallel with age the skin becomes more sensitivetowards disturbing influences, either intrinsic or extrinsic, which mayresult in itch, redness or even darker spots, particular on hands andthe facial area due to pigmentation disorders. These unwanted signs maylead to an undesired age judgment of a person.

Cosmetic preparations are essentially useful for skin care. One aim ofskin care in the cosmetic sense is to strengthen or rebuild the skin'snatural function as a barrier against environmental influences (e.g.UV-light, dirt, chemicals, microorganisms) and against the loss ofendogenous substances (e.g. water, natural lipids, electrolytes). Ifthis function becomes impaired, increased resorption of toxic orallergenic substances or attack by microorganisms may result, leading totoxic or allergic skin reactions.

Another aim of skin care is to compensate for the loss by the skin oflipids and water caused by daily washing. This is particularlyimportant, if the natural regeneration ability is inadequate.Furthermore, skin care products should protect against environmentalinfluences, in particular against sun and wind, and delay skin aging.

Strengthening or thickening of the epidermis together with an optimizedskin barrier lipid synthesis can rebuild the skin's barrier ability andis therefore of significant cosmetic value. Reduced transepidermal waterloss (TEWL) is a sign of an intact lipid barrier, which acts also asfirst defense line to protect against the appearance of skin wrinkles.

Another strategy to fight wrinkles is to stimulate the collagensynthesis in the dermis. A number of degenerative processes act on thecollagen matrix and is triggered by extrinsic factors like UV radiation,pollution in general and particular cigarette smoke or intrinsic factorsleading to any chronic or sub chronic inflammation. Destruction and/orimpaired repair efficacy leads to a denser and less elastic macrostructure of the dermis, which in turn leads to the formation of deepwrinkles. Enhancing the de novo synthesis of collagen or otherstructural proteins of the dermis is considered a valuable therapy toreduce the existing wrinkles and to protect against the appearance ofnew wrinkles.

Of particular importance for anti-aging cosmetics is to inhibit thesenescence of skin cells in order to keep their regular metabolic levelon a constant and beneficial level.

Hair loss or alopecia is a common affliction of humans. The most commonform of hair loss in both males and females is patterned baldness orandrogenic alopecia.

Hair follicles range in size from small, superficial, vellus folliclesto large, deep, terminal follicles. The cyclic growth phases of hairfollicles are telogen (resting), anagen I-III (developing), anagen IV-VI(growing) and catagen (involuting).

In the development of androgenic alopecia there is the gradualdiminution of follicle size, with conversion of large, terminalfollicles, producing thick, pigmented hair fibers (terminal hair) tosmall vellus follicles producing fine, non-pigmented hair fibers (vellushair). In addition, the proportion of growing anagen follicles declines.

There exists a wide variety of literature regarding cosmeticpreparations, in particular regarding cosmetic preparations for treatingwrinkles and for promoting hair growth. As examples of the extensiveliterature it can be referred e.g. to GB 906,000, EP-A 699 429 or WO03/086342.

While a variety of technologies exist to prevent and to fight the signsof skin aging, to improve the appearance of the skin or to treat orprevent hair loss, there is still a demand for more efficaciousingredients.

The problem to be solved by the present invention is the provision ofnovel compounds, of compositions containing these novel compounds, inparticular of cosmetic preparations which are particularly useful fortreating and/or preventing wrinkles, thickening of the epidermis, andpreventing and/or treating of hair loss, but also preparations which areuseful against other conditions which are observed with skin aging dueto environmental or other external influences or due to age. The newcompounds should have an activity which is comparable to the activity ofknown cosmetically active compounds but preferably is better than theactivity of the prior art compounds.

This problem is solved on the basis of the unexpected finding thatcertain arylalkyl carboxylic acylates with naturally occurring,non-toxic hydroxyl, sulfhydryl, amino or imino compounds show activityin cosmetic applications and related pharmaceutical applications, inparticular for treating and preventing wrinkles and hair loss andthickening the epidermis, but also for ameliorating the effects of agingof the skin, which may be caused by external or environmental hazards orby the natural aging of the skin.

Accordingly, in one aspect, the present invention is concerned withcompounds represented by general formula (I) as shown above. In anotheraspect, the invention is concerned with compositions, particularlycosmetic preparations comprising a compound of the formula (I). In stillanother aspect, the invention is concerned with the use of the compoundsof formula (I) for treating and preventing wrinkles and hair loss andthickening the epidermis, but also for ameliorating the effects of agingof the skin, which may be caused by external or environmental hazards orby the natural aging of the skin, and with a method of treating andpreventing the aforesaid conditions by administering an effective amountof a topical composition comprising a compound of formula (I) on theappropriate portions of the skin of an individual in need of suchtreatment.

In another embodiment, the invention relates to a method of treatment orprophylaxis of wrinkles or dry skin or sensitive skin or any symptomscaused by negative developments of the physiological homeostasis ofhealthy skin, promotion of hair growth, protection from hair loss, athickening of the epidermis, anti-acne, the inhibition of senescence ofskin cells, prevention or treatment of photo damage, prevention ortreatment of oxidative stress phenomena, prevention or treatment ofcellulite, prevention or treatment of pigmentation disorders and/or eventhe skin tone, prevention and treatment of disturbances in ceramide andlipid synthesis, prevention of excess sebum production, reduction ofactivities of matrix metallo proteases or other proteases in the skin,treatment and prevention of inflammatory skin conditions includingatopic eczema, polymorphic light eruption, psoriasis, vertiligo,prevention and treatment of itchy or irritated skin, which comprisesapplying an effective amount of composition comprising a compound offormula (I) on the appropriate portions of the skin of the individual inneed of such treatment.

The term ‘an effective amount’ refers to an amount necessary to obtain aphysiological effect. The physiological effect may be achieved by onesingle application or by repeated applications. The dosage applied may,of course, vary depending upon known factors, such as the physiologicalcharacteristics of the particular composition and its mode and route ofadministration; the age, health and weight of the recipient; the natureand extent of the symptoms; the kind of concurrent treatment; thefrequency of treatment; the concentration of the compound of formula (I)in the topical composition; and the effect desired and can be adjustedby a person skilled in the art.

The amount of the topical composition which is to be applied to the skindepends on the concentration of the active ingredients, i.e. thecompound of formula (I), in the compositions and the desired cosmetic orpharmaceutical effect. For example, application can be such that a crèmeis applied to the skin. A crème is usually applied in an amount of 2 mgcrème/cm² skin. The amount of the composition which is applied to theskin is, however, not critical, and if with a certain amount of appliedcomposition the desired effect cannot be achieved, a higherconcentration of the active ingredients can be used e.g. by applyingmore of the composition or by applying compositions which contain moreactive ingredient.

A preferred group of compounds within the scope of formula (I) are thosewherein Ph is unsubstituted phenyl. If Ph is substituted phenyl, thephenyl ring may be substituted by up to three substituents which areselected, independently, from hydroxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₁-C₆ alkoxy and C₂-C₆ alkenyloxy. Preferred substituted phenyl moietiesare phenyl mono-substituted by C₁₋₆-alkoxy, especially methoxyphenyl.

In all embodiments of the invention compounds within the scope offormula (I) wherein m is 1 are preferred. Most preferred according tothe invention are compounds within the scope of formula (I) wherein theresidue [Ph-(CH₂)_(n)—CO]_(m) is derived from phenyl butyric acid and mis 1.

The naturally occurring, non-toxic compound carrying at least onehydroxyl, sulfhydryl, amino or imino group from which the moiety X informula (I) is derived may be any such compound that can be used incosmetic applications. Examples of such compounds are fat-solublevitamin derivatives and analogues thereof, water-soluble vitamins,derivatives or analogues thereof, carbohydrates, α-hydroxy-carboxylicacids, aliphatic alcohols and polyols, amino alcohols, chromanes andflavones, derivatives and analogues thereof, pyrimidines or purines oranalogues thereof, terpenes, and catechols; particular examples being(CAS numbers given in parenthesis) glucoses with open or ring form(50-99-7), Tocopherols like DL-α-tocopherol (10191-41-0), Panthenol(81-13-0), Pantothenic acid (79-83-4), Pyridoxines such as vitamin B₆(65-23-6), Kinetin (525-79-1), Vanillin (121-33-5), Fenchol (1632-73-1),Quercetin (117-39-5), Wogonin (632-85-9), Delphinidin (528-53-0),Silymarin (65666-07-1), Gossypin (652-78-8), Equol (531-95-3), ShikimicAcid (138-59-0), Gramin (87-52-5), Carnitin (461-06-3), Glutathion(70-18-8), Ginkgetin (481-46-9), Insulin (11061-68-0), Farnesol(106-28-5), Thiamine (67-03-8), Riboflavin (83-88-5), Bisabolol(23089-26-1), Ascorbic Acid (50-81-7), Stay-C 50 (66170-10-3), FolicAcid (59-30-3), Daidzein (486-66-8), Genistein (446-72-0), Resveratrol(501-36-0), Betanin (7659-95-2), Phytantriol (74563-64-7), Retinol(68-26-8), Vitamin D3 (67-97-0), Hy-D (63283-36-3), Astaxanthin(754245-2), Lutein (127-40-2), Zeaxanthin (144-68-3), alpha-hydroxyphytanic acid (14721-68-7), beta-Sitosterol (64997-52-0), Menthol(89-78-1), Allantoin (97-59-6), epigallocatechin gallate (EGCG)(989-51-5), Glycerol (56-81-5), Phytol (150-86-7), lactic acid(50-21-5), Biotin (58-85-5), phytanic acid (14721-66-5) andtetradecylthioacetic acid (2921-20-2).

Preferably, the naturally occurring, non-toxic compound carrying atleast one hydroxyl, sulfhydryl, amino or imino group from which themoiety X in formula (I) is derived is

a fat-soluble vitamin or derivative or analogue, in particular atocopherol, a carotenoid and vitamin D3 or a hydroxyl derivativethereof;a water-soluble vitamin, derivatives or analogues thereof belonging tothe vitamin B or vitamin C group, in particular panthenol, pantothenicacid, pyridoxines, thiamine, riboflavin, nicotinamide,2-hydroxyethylnicotinamide, folic acid, ascorbic acid or ascorbic acidphosphate, more in particular nicotinamide, 2-hydroxyethylnicotinamide,panthenol, ascorbic acid or ascorbic acid phosphate;a chromane, flavone, derivatives and analogues thereof, in particularequol, quercetin, delphinidine, silymarin, daidzein, or genistein;a pyrimidine or purine or analogue thereof, in particular kinetin orallantoin;a terpene preferably farnesol, bisabolol, phytol and menthol, inparticular bisabolol; ora catechol, in particular epigallocatechingallate.

Of particular interest as compounds from which the moiety X is derived,i.e. compounds of the formula XH, are panthenol, bisabolol, kinetin and2-hydroxyethylnicotinamide.

Further examples of compounds of formula (I) are the phenyl butyric acidester of nicotinic acid 2-hydroxyethylamide,glycerol-1-phenylbutyrate-3-nicotinate and the phenyl acetic acid esterof phytanic acid 2-hydroxyethylamide.

Especially preferred according to the invention are the followingcompounds of formula (I):

-   4-phenylbutyric acid 2-[(pyridine-3-carbonyl)amino]-ethyl ester-   4-phenylbutyric acid    3-(2,4-dihydroxy-3,3-dimethyl-butyrylamino)-propyl ester.-   N-furan-2-yl-methyl-4-phenyl-N-(9H-purin-6-yl)-butyramide-   4-phenylbutyric acid    1,5-dimethyl-1-(4-methyl-cyclohex-3-enyl)-hex-4-enyl ester.

In accordance of the present invention, the compounds of formula (I) canbe prepared in a manner known per se, e.g. as disclosed in the Examplesor in analogy thereto. Generally, the compounds of formula (I) can beprepared by acylating a compound of the formula XH, wherein X is asdefined above, with a compound of the formula Ph-(CH₂)_(n)—COOH or areactive derivative thereof.

The acylation of the present invention can be carried out in a mannerknown per se. Suitably, the acylation is carried out using a reactivederivate such as a halogenide, e.g. the chloride or bromide, in thepresence of an organic base, e.g. pyridine or an aliphatic amine such astriethylamine, or an inorganic base such as sodium hydride or an alkalicarbonate. If required, any groups reactive to the acylating agent whichare not intended to be acylated have to be protected. Therefore theacylation of polyfunctional molecules requires versatile protectinggroups that can be easily introduced which are orthogonally stable toeach other and can be selectively removed under mild conditions. A goodselection of the most useful protecting groups for functional andpotentially reactive groups which can be easily applied for the abovementioned purpose by people skilled in the art can be found e.g. in P.J. Kocienski, Protecting Groups, 2000, Corrected Edition, Georg ThiemeVerlag, Stuttgart, N.Y. and T. W. Greene, P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Edition, 1999, John Wiley & Sons,Inc., New York.

For instance, when acylating panthenol, the primary and secondaryhydroxy groups located in the carboxylic acid portion of the moleculemay be protected by forming an acetonide, thus allowing a selectiveacylation of the hydroxy group located in the amide portion of themolecule. On the other hand, the acylation of compounds of the formulaXH which carry more than one reactive OH, SH, amino or imino group maybe carried out without intermediary protection of individual reactivegroups, thus leading to compounds of the formula (I) wherein m is aninteger of greater than 1 with m corresponding to the number of reactiveOH, SH, amino or imino groups in the starting compound of formula XH.

For the purposes of the present invention, the compounds of formula (I)can be used alone or in mixtures.

The present invention also provides compositions, in particular topicalcompositions comprising at least one compound represented by generalformula (I), and a cosmetically acceptable excipient or diluent.

In case that the compounds of formula I bear one or more chiral centersthe compounds represented by general formula (I) may be present in aracemic mixture, in a mixture of diastereomers or in excess of anenantiomer and/or diastereomer. If one or more chiral centers arepresent the optical purity of the mixture is preferably ≧80% ee, morepreferably ≧90% ee, most preferably ≧95% de. If two or more chiralcenters are present the purity of the mixture is preferably ≧80% de,more preferably ≧90% de, most preferably ≧95% de.

The compositions of the present invention are pharmaceutical or cosmeticcompositions, preferably cosmetic compositions or cosmetic preparations.

The term “cosmetic preparation” or “cosmetic composition” as used in thepresent application refers to cosmetic compositions as defined under theheading “Kosmetika” in Römpp Lexikon Chemie, 10th edition 1997, GeorgThieme Verlag Stuttgart, N.Y.

The compositions of the present invention contain the compoundrepresented by general formula (I) with cosmetically acceptableexcipients or diluents. If nothing else is stated, the excipients,additives, diluents, etc. mentioned in the following are suitable forcosmetic compositions.

If nothing else is stated, in this application parts and percentages areper weight and are based on the weight of the composition.

Preferably, the cosmetic or pharmaceutical compositions of the presentinvention are topical compositions in the form of a suspension ordispersion in solvents or fatty substances, or alternatively in the formof an emulsion or micro emulsion (in particular of O/W or W/O type,O/W/O or W/O/W-type), PET-emulsions, multiple emulsions, bickeringemulsions, hydrogels, alcoholic gels, lipogels, one or multiphasesolutions or a vesicular dispersion and other usual compositions, whichcan also be applied by pens, as masks or as sprays. The emulsions canalso contain anionic, nonionic, cationic or amphoteric surfactant(s).

Preferred compositions according to the invention are skin carepreparations, hair-care preparations, decorative preparations, lightprotection preparations and functional preparations.

Examples of skin care preparations are, in particular, body oils, bodylotions, body gels, treatment creams, skin protection ointments, shavingpreparations, such as shaving foams or gels, skin powders such as babypowder, moisturizing gels, moisturizing sprays, revitalizing bodysprays, cellulite gels, anti acne preparations and peeling preparations.

Examples of hair care preparations are, for example, hair-washingpreparations in the form of shampoos, hair conditioners, hair-carepreparations, e.g. treatment preparations, pre-treatment preparations,hair tonics, styling creams, styling gels, pomades, hair rinses,treatment packs, intensive hair treatments, hair-straighteningpreparations, liquid hair-setting preparations, hair foams andhairsprays and lacquers, perming agents, hair gels, hair fixatives andhair dying or bleaching agents.

Examples of decorative preparations are in particular lipstick, eyeshadow, mascaras, dry and moist make-up, rouge, powders, and suntanlotions.

Examples of functional preparations are cosmetic or pharmaceuticalcompositions containing active ingredients such as hormone preparations,vitamin preparations, vegetable extract preparations, anti-ageingpreparations, and antimicrobial (antibacterial or antifungal)preparations without being limited thereto.

Cosmetic compositions in accordance with the invention can be in theform of a liquid, lotion, a thickened lotion, a gel, a cream, a milk, anointment, a paste, a powder, a make-up, or a solid tube stick and can beoptionally be packaged as an aerosol and can be provided in the form ofa mousse such as a aerosol mousse, a foam or a spray foams, sprays,sticks, a gel, a plaster, a powder, a cleanser, a soap or aerosols orwipes.

The compositions of the invention can also contain usual cosmeticadjuvants and additives, such as preservatives/antioxidants, fattysubstances/oils, water, organic solvents, silicones, thickeners,softeners, emulsifiers, sunscreens, cosmetic actives antifoaming agents,moisturizers, fragrances, surfactants, fillers, sequestering agents,anionic, cationic, nonionic or amphoteric polymers or mixtures thereof,propellants, acidifying or basifying agents, dyes, colorants, pigmentsor nanopigments, e.g. those suited for providing a photoprotectiveeffect by physically blocking out ultraviolet radiation, or any otheringredients usually formulated into cosmetics. A good overview ofsuitable additives for cosmetic compositions can also be found e.g. inWO 03/082232. The additives disclosed in this document, in particularthe waxes, thickeners, structuring agents, film forming agents andconditioning ingredients are also suitable for the compositions of thepresent invention and included herein by reference. Of course, thestabilizing compositions disclosed in this document can also be used forpreparing the compositions of the present invention.

The composition of the present invention can also contain one or moreadditional pharmaceutically or cosmetically active ingredients, inparticular for preventing or reducing acne, wrinkles, lines,pigmentation, atrophy, inflammation, as well as topical anesthetics,artificial tanning agents and accelerators, antimicrobial agents, andantifungal agents and sun screening additives without being limitedthereto.

Examples of such ingredients are peptides (e.g., Matrixyl™ [pentapeptidederivative]), oligopeptides, wax-based synthetic peptides (e.g., octylpalmitate and tribehenin and sorbitan isostearate andpalmitoyl-oligopeptide), glycerol, urea, guanidine (e.g. aminoguanidine); vitamins and derivatives thereof such as vitamin C (ascorbicacid), vitamin A (e.g., retinoid derivatives such as retinyl palmitateor retinyl propionate), vitamin E (e.g., tocopherol acetate), vitamin B₃(e.g. nicotinamide) and vitamin B₅ (e.g. panthenol), vitamin B₆ andvitamin B₁₂, biotin, folic acid; anti-acne actives or medicaments (e.g.resorcinol, salicylic acid, and the like); antioxidants (e.g.phytosterols, lipoic acid); flavonoids (e.g. isoflavones,phytoestrogens); skin soothing and healing agents such as aloe veraextract, allantoin and the like; agents suitable for aesthetic purposessuch as essential oils, fragrances, skin sensates, opacifiers, aromaticcompounds (e.g., clove oil, menthol, camphor, eucalyptus oil, andeugenol), desquamatory actives, hydroxy acids such as AHA acids, radicalscavengers, farnesol, antifungal actives in particular bisabolol,alkyldiols such as 1,2-pentanediol, hexanediol or 1,2-octanediol,phytol, polyols such as phytanetriol, ceramides and pseudoceramides,amino acids, protein hydrolysates, polyunsaturated fatty acids, plantextracts like kinetin, DNA or RNA and their fragmentation products,carbohydrates, conjugated fatty acids, carnitin, carnosine, biochinonen,phytofluen, phytoen, and their corresponding derivatives.

Additionally the cosmetic and pharmaceutical topical composition of thepresent invention may contain UV-screening agents (UV-filter). Theadditional UV-screening agents are advantageously selected from IR,UV-A, UV-B, UV-C and/or broadband filters. Examples of UV-B or broadspectrum screening agents, i.e. substances having absorption maximumsbetween about 290 nm and 340 nm may be organic or inorganic compounds.Organic UV-B or broadband screening agents are e.g. acrylates such as2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL® 340),ethyl 2-cyano-3,3-diphenylacrylate and the like; camphor derivativessuch as 4-methyl benzylidene camphor (PARSOL® 5000), 3-benzylidenecamphor, camphor benzalkonium methosulfate, polyacrylamidomethylbenzylidene camphor, sulfo benzylidene camphor, sulphomethyl benzylidenecamphor, therephthalidene dicamphor sulfonic acid and the like;Cinnamate derivatives such as ethylhexyl methoxycinnamate (PARSOL® MCX),ethoxyethyl methoxycinnamate, diethanolamine methoxycinnamate (PARSOL®Hydro), isoamyl methoxycinnamate and the like as well as cinnamic acidderivatives bond to siloxanes; p-aminobenzoic acid derivatives, such asp-aminobenzoic acid, 2-ethylhexyl p-dimethylaminobenzoate,N-oxypropylenated ethyl p-aminobenzoate, glyceryl p-aminobenzoate;benzophenones such as benzophenone-3,benzophenone-4,2,2′,4,4′-tetrahydroxy-benzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone and the like; esters ofbenzalmalonic acid such as di-(2-ethylhexyl) 4-methoxybenzalmalonate;esters of 2-(4-ethoxy-anilinomethylene)propandioic acid such as2-(4-ethoxy anilinomethylene) propandioic acid diethyl ester asdescribed in the European Patent Publication EP 0895 776; organosiloxanecompounds containing benzmalonate groups as described in the EuropeanPatent Publications EP 0358584 B1, EP 0538431 B1 and EP 0709080 A1 suchas PARSOL® SLX; drometrizole trisiloxane (Mexoryl XL); imidazolederivatives such as e.g. 2-phenyl benzimidazole sulfonic acid and itssalts (PARSOL®HS). Salts of 2-phenyl benzimidazole sulfonic acid aree.g. alkali salts such as sodium- or potassium salts, ammonium salts,morpholine salts, salts of primary, sec. and tert. amines likemonoethanolamine salts, diethanolamine salts and the like; salicylatederivatives such as isopropylbenzyl salicylate, benzyl salicylate, butylsalicylate, ethylhexyl salicylate (PARSOL® EHS, Neo Heliopan OS),isooctyl salicylate or homomethyl salicylate (homosalate, PARSOL® HMS,Neo Heliopan HMS) and the like; triazine derivatives such as ethylhexyltriazone (Uvinul T-150), diethylhexyl butamido triazone (Uvasorb HEB)and the like. Encapsulated UV-filters such as encapsulated ethylhexylmethoxycinnamate (Eusolex UV-pearls) or microcapsules loaded withUV-filters as e.g. disclosed in EP 1471995 and the like;

Examples of broad spectrum or UV A screening agents i.e. substanceshaving absorption maximums between about 320 nm and 400 nm may beorganic or inorganic compounds. Organic broad spectrum or UV A screeningagents include e.g. dibenzoylmethane derivatives such as4-tert.-butyl-4′-methoxydibenzoyl-methane (PARSOL® 1789),dimethoxydibenzoylmethane, isopropyldibenzoylmethane and the like;benzotriazole derivatives such as2,2′-methylene-bis-(6-(2H-benzotriazole-2-yl)-4-(1,1,3,3-tetramethylbutyl)-phenol(Tinosorb M) and the like; bis-ethylhexyloxyphenol methoxyphenyltriazine (Tinosorb S) and the like;phenylene-1,4-bis-benzimidazolsulfonic acids or salts such as2,2-(1,4-phenylene)bis-(1H-benzimidazol-4,6-disulfonic acid)(Neoheliopan AP); amino substituted hydroxybenzophenones such as2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester (Uvinul Aplus) as described in the European Patent Publication EP 1046391; IonicUV-A filters as described in the International Patent PublicationWO2005080341 A1; As dibenzoylmethane derivatives have limitedphotostability it may be desirable to photostabilize these UV-Ascreening agents. Thus, the term “conventional UV-A screening agent”also refers to dibenzoylmethane derivatives such as e.g. PARSOL® 1789stabilized by, e.g. 3,3-Diphenylacrylate derivatives as described in theEuropean Patent Publications EP 0 514 491 B1 and EP 0 780 119 A1;Benzylidene camphor derivatives as described in the U.S. Pat. No.5,605,680; Organosiloxanes containing benzmalonate groups as describedin the European Patent Publications EP 0358584 B1, EP 0538431 B1 and EP0709080 A1.

A good overview of UV-A- and UV-B screening agents which can be added tothe compositions of the present invention can also be found in DE-A 10327 432. All UV-screening agents disclosed in this document are alsouseful as components for the compositions of the present invention andare included herein by reference.

A safe and effective amount of the UV-screening agent is used, typicallyfrom about 1 wt.-% to about 20 wt.-%, more typically from about 2 wt.-%to about 10 wt.-%.

Other suitable UV-screening agents which may be incorporated into thecosmetic or pharmaceutical topical compositions of the present inventionare inorganic pigments such as microparticulated metal oxides (e.g.PARSOL® TX). Examples of such compounds include e.g. titanium dioxidehaving an average primary particle size of from about 15 nm to about 100nm, zinc oxide having an average primary particle size of from about 15nm to about 150 nm, zirconium oxide having an average primary particlesize of from about 15 nm to about 150 nm, iron oxide having an averageprimary particle size of from about 15 nm to about 500 nm, and mixturesthereof. The metal oxide particles may also be coated by metal oxidessuch as e.g. aluminum or zirconium oxides or by organic coatings such ase.g. polyols, methicone, aluminum stearate, alkyl silane. Such coatingsare well known in the art. When used herein, the inorganic sunscreensare present in the amount of from about 0.1 wt.-% to about 20 wt.-%,preferably from about 0.5 wt.-% to about 10 wt.-%, more preferably fromabout 1 wt.-% to about 5 wt.-%.

The compositions of the present invention preferably contain one or moreantioxidants/preservatives. Based on the invention all knownantioxidants usually formulated into cosmetics can be used. Especiallypreferred are antioxidants chosen from the group consisting of aminoacids (e.g. glycine, histidine, tyrosine, tryptophan) and theirderivatives, imidazole (e.g. urocanic acid) and derivatives, peptidessuch as D,L-carnosine, D-carnosine, L-carnosine and derivatives (e.g.anserine), carotenoids, carotenes (e.g. α-carotene, β-carotene,lycopene) and derivatives, chlorogenic acid and derivatives, lipoic acidand derivatives (e.g. dihydrolipoic acid), aurothioglucose,propylthiouracil and other thiols (e.g. thioredoxine, glutathione,cysteine, cystine, cystamine and its glycosyl-, N-acetyl-, methyl-,ethyl-, propyl-, amyl-, butyl- and lauryl-, palmitoyl-; oleyl-,y-linoleyl-, cholesteryl- and glycerylester) and the salts thereof,dilaurylthiodipropionate, distearylthiodipropionate, thiodipropionicacid and its derivatives (ester, ether, peptides, lipids, nucleotides,nucleosides and salts) as well as sulfoximine compounds (such asbuthioninsulfoximine, homocysteinsulfoximine, buthioninsulfone, penta-,hexa-, heptathioninsulfoximine) in very low compatible doses (e.g. pmolto μmol/kg), additionally (metal)-chelators (such as α-hydroxyfattyacids, palmic-, phytinic acid, lactoferrin), α-hydroxyacids (such ascitric acid, lactic acid, malic acid), huminic acid, gallic acid, gallicextracts, bilirubin, biliverdin, EDTA, EGTA and its derivatives,unsaturated fatty acids and their derivatives (such as γ-linoleic acid,linolic acid, oleic acid), folic acid and its derivatives, ubiquinoneand ubiquinol and their derivatives, vitamin C and derivatives (such asascorbylpalmitate and ascorbyltetraisopalmitate, Mg-ascorbylphosphate,Na-ascorbylphosphate, ascorbylacetate, ascorbylglucoside), tocopheroland derivates (such as vitamin-E-acetate), mixtures of nat. vitamin E,vitamin A and derivatives (vitamin-A-palmitate and -acetate) as well asconiferylbenzoate, rutinic acid and derivatives, α-glycosylrutin,ferulic acid, furfurylidenglucitol, carnosin, butylhydroxytoluene,butylhydroxyanisole, trihydroxybutyrophenone, urea and its derivatives,mannose and derivatives, zinc and derivatives (e.g. ZnO, ZnSO₄),selenium and derivatives (e.g. selenomethionine), stilbenes andderivatives (such as stilbenoxide, trans-stilbenoxide) and suitablederivatives (salts, esters, ethers, sugars, nucleotides, nucleosides,peptides and lipids) of the named active ingredients. One or morepreservatives/antioxidants may be present in an amount about 0.01 wt. %to about 10 wt. % of the total weight of the composition of the presentinvention. Preferably, one or more preservatives/antioxidants arepresent in an amount about 0.1 wt. % to about 1 wt. %.

Typically topical compositions also contain surface active ingredientslike emulsifiers, solubilizers and the like. An emulsifier enables twoor more not miscible components to be combined homogeneously. Moreover,the emulsifier acts to stabilize the composition. Emulsifiers that maybe used in the present invention in order to form O/W, W/O, O/W/O orW/O/W emulsions/microemulsions include sorbitan oleate, sorbitansesquioleate, sorbitan isostearate, sorbitan trioleate,polyglyceryl-3-diisostearate, polyglycerol esters of oleic/isostearicacid, polyglyceryl-6 hexaricinolate, polyglyceryl-4-oleate,polyglyceryl-4 oleate/PEG-8 propylene glycol cocoate, oleamide DEA, TEAmyristate, TEA stearate, magnesium stearate, sodium stearate, potassiumlaurate, potassium ricinoleate, sodium cocoate, sodium tallowate,potassium castorate, sodium oleate, and mixtures thereof. Furthersuitable emulsifiers are phosphate esters and the salts thereof such ascetyl phosphate (Amphisol® A), diethanolamine cetyl phosphate(Amphisol®), potassium cetyl phosphate (Amphisol® K), sodium glyceryloleate phosphate, hydrogenated vegetable glycerides phosphate andmixtures thereof. Furthermore, one or more synthetic polymers may beused as an emulsifier. For example, PVP eicosene copolymer,acrylates/C₁₀₋₃₀ alkyl acrylate crosspolymer, acrylates/steareth-20methacrylate copolymer, PEG-22/dodecyl glycol copolymer, PEG-45/dodecylglycol copolymer, and mixtures thereof. The preferred emulsifiers arecetyl phosphate (Amphisol® A), diethanolamine cetyl phosphate(Amphisol®), potassium cetyl phosphate (Amphisol® K), PVP Eicosenecopolymer, acrylates/C₁₀₋₃₀-alkyl acrylate crosspolymer, PEG-20 sorbitanisostearate, sorbitan isostearate, and mixtures thereof. The one or moreemulsifiers are present in a total amount about 0.01 wt. % to about 20wt. % of the total weight of the composition of the present invention.Preferably, about 0.1 wt. % to about 10 wt. % of emulsifiers are used.

The lipid phase of the topical compositions can advantageously be chosenfrom mineral oils and mineral waxes; oils such as triglycerides ofcaprinic acid or caprylic acid, preferable castor oil; oils or waxes andother natural or synthetic oils, in an preferred embodiment esters offatty acids with alcohols e.g. isopropanol, propylene glycol, glycerinor esters of fatty alcohols with carboxylic acids or fatty acids;alkylbenzoates; and/or silicone oils such as dimethylpolysiloxane,diethylpolysiloxane, diphenylpolysiloxane, cyclomethicones and mixturesthereof.

Exemplary fatty substances which can be incorporated in the oil phase ofthe emulsion, micro-emulsion, oleo gel, hydrodispersion orlipodispersion of the present invention are advantageously chosen fromesters of saturated and/or unsaturated, linear or branched alkylcarboxylic acids with 3 to 30 carbon atoms, and saturated and/orunsaturated, linear and/or branched alcohols with 3 to 30 carbon atomsas well as esters of aromatic carboxylic acids and of saturated and/orunsaturated, linear or branched alcohols of 3-30 carbon atoms. Suchesters can advantageously be selected from octylpalmitate, octylcocoate,octylisostearate, octyldodecylmyristate, cetearylisononanoate,isopropyl-myristate, isopropylpalmitate, isopropylstearate,isopropyloleate, n-butylstearate, n-hexyllaureate, n-decyloleat,isooctylstearate, isononylstearate, isononylisononanoate, 2-ethylhexylpalmitate, 2-ethylhexyllaurate, 2-hexyldecylstearate,2-octyldodecylpalmitate, stearylheptanoate, oleyloleate, oleylerucate,erucyloleate, erucylerucate, tridecylstearate, tridecyltrimellitate, aswell as synthetic, half-synthetic or natural mixtures of such esterse.g. jojoba oil.

Other fatty components suitable for use in the topical compositions ofthe present invention include polar oils such as lecithins and fattyacid triglycerides, namely triglycerol esters of saturated and/orunsaturated, straight or branched carboxylic acid with 8 to 24 carbonatoms, preferably of 12 to 18 carbon-atoms whereas the fatty acidtriglycerides are preferably chosen from synthetic, half synthetic ornatural oils (e.g. cocoglyceride, olive oil, sun flower oil, soybeanoil, peanut oil, rape seed oil, sweet almond oil, palm oil, coconut oil,castor oil, hydrogenated castor oil, wheat oil, grape seed oil,macadamia nut oil and others); apolar oils such as linear and/orbranched hydrocarbons and waxes e.g. mineral oils, vaseline(petrolatum); paraffins, squalane and squalene, polyolefins,hydrogenated polyisobutenes and isohexadecanes, favored polyolefins arepolydecenes; dialkyl ethers such as dicaprylylether; linear or cyclicsilicone oils such as preferably cyclomethicone(octamethylcyclotetrasiloxane; cetyldimethicone,hexamethylcyclotri-siloxane, polydimethylsiloxane,poly(methylphenylsiloxane) and mixtures thereof.

Other fatty components which can advantageously be incorporated intopical compositions of the present invention are isoeikosane;neopentylglycoldiheptanoate; propyleneglycol-dicaprylate/dicaprate;caprylic/capric/diglycerylsuccinate; butyleneglycol caprylat/caprat;C₁₂₋₁₃-alkyllactate; di-C₁₂₋₁₃ alkyltartrate; triisostearin;dipentaerythrityl hexacaprylat-/hexacaprate;propylenglycolmonoisostearate; tricaprylin; dimethylisosorbid.Especially beneficial is the use of mixtures C₁₂₋₁₅-alkylbenzoate and2-ethylhexylisostearate, mixtures C₁₂₋₁₅-alkylbenzoate andisotridecylisononanoate as well as mixtures of C₁₂₋₁₅-alkylbenzoate,2-ethylhexylisostearate and isotridecylisononanoate.

The oily phase of the compositions of the present invention can alsocontain natural vegetable or animal waxes such as bee wax, china wax,bumblebee wax and other waxes of insects as well as shea butter andcocoa butter.

A moisturizing agent may be incorporated into a topical composition ofthe present invention to maintain hydration or rehydrate the skin.Moisturizers that prevent water from evaporating from the skin byproviding a protective coating are called emollients. Additionally anemollient provides a softening or soothing effect on the skin surfaceand is generally considered safe for topical use. Preferred emollientsinclude mineral oils, lanolin, petrolatum, capric/caprylictriglyceraldehydes, cholesterol, silicones such as dimethicone,cyclomethicone, almond oil, jojoba oil, avocado oil, castor oil, sesameoil, sunflower oil, coconut oil and grape seed oil, cocoa butter, oliveoil aloe extracts, fatty acids such as oleic and stearic, fatty alcoholssuch as cetyl and hexadecyl (ENJAY), diisopropyl adipate,hydroxybenzoate esters, benzoic acid esters of C₉₋₁₅-alcohols, isononyliso-nonanoate, ethers such as polyoxypropylene butyl ethers andpolyoxypropylene cetyl ethers, and C₁₂₋₁₅-alkyl benzoates, and mixturesthereof. The most preferred emollients are hydroxybenzoate esters, aloevera, C₁₂₋₁₅-alkyl benzoates, and mixtures thereof. An emollient ispresent in an amount of about 1 wt. % to about 20 wt. % of the totalweight of the composition. The preferred amount of emollient is about 2wt. % to about 15 wt. %, and most preferably about 4 wt. % to about 10wt. %.

Moisturizers that bind water, thereby retaining it on the skin surfaceare called humectants. Suitable humectants can be incorporated into atopical composition of the present invention such as glycerin,polypropylene glycol, 1,2-pentandiol, polyethylene glycol, lactic acid,pyrrolidone carboxylic acid, urea, phospholipids, collagen, elastin,ceramides, lecithin sorbitol, PEG-4, and mixtures thereof. Additionalsuitable moisturizers are polymeric moisturizers of the family of watersoluble and/or swellable/and/or with water gelating polysaccharides suchas hyaluronic acid, chitosan and/or a fucose rich polysaccharide whichis e.g. available as Fucogel®1000 (CAS-Nr. 178463-23-5) by SOLABIA S.One or more humectants are optionally present at about 0.5 wt. % toabout 8 wt. % in a composition of the present invention, preferablyabout 1 wt. % to about 5 wt. %.

The aqueous phase of the preferred topical compositions of the presentinvention can contain the usual cosmetic or pharmaceutical additivessuch as alcohols, especially lower alcohols, preferably ethanol and/orisopropanol, low diols or polyols and their ethers, preferablypropyleneglycol, glycerin, ethyleneglycol, ethyleneglycol monoethyl- ormonobutylether, propyleneglycol monomethyl- or -monoethyl- or-monobutylether, diethyleneglycol monomethyl- or -monoethylether andanalogue products, polymers, foam stabilizers; electrolytes andespecially one or more thickeners. Thickeners that may be used incompositions of the present invention to assist in making theconsistency of a product suitable include carbomer, siliciumdioxide,magnesium and/or aluminum silicates, beeswax, stearic acid, stearylalcohol polysaccharides and their derivatives such as xanthan gum,hydroxypropyl cellulose, polyacrylamides, acrylate crosspolymerspreferably a carbomer, such as Carbopole® of type 980, 981, 1382, 2984,5984 alone or mixtures thereof. Suitable neutralizing agents which maybe included in the composition of the present invention to neutralizecomponents such as e.g. an emulsifier or a foam builder/stabilizerinclude but are not limited to alkali hydroxides such as a sodium andpotassium hydroxide; organic bases such as diethanolamine (DEA),triethanolamine (TEA), aminomethyl propanol, and mixtures thereof; aminoacids such as arginin and lysine and any combination of any foregoing.The neutralizing agent can be present in an amount of about 0.01 wt. %to about 8 wt. % in the composition of the present invention,preferably, 1 wt. % to about 5 wt. %.

The addition of electrolytes into the composition of the presentinvention may be necessary to change the behavior of a hydrophobicemulsifier. Thus, the emulsions/microemulsions of this invention maycontain preferably electrolytes of one or several salts including anionssuch as chloride, sulfates, carbonate, borate and aluminate, withoutbeing limited thereto. Other suitable electrolytes can be on the basisof organic anions such as, but not limited to, lactate, acetate,benzoate, propionate, tartrate and citrate. As cations preferablyammonium, alkylammonium, alkali- or alkaline earth metals, magnesium-,iron- or zinc-ions are selected. Especially preferred salts arepotassium and sodium chloride, magnesium sulfate, zinc sulfate andmixtures thereof. Electrolytes can be present in an amount of about 0.01wt. % to about 8 wt. % in the composition of the present invention.

The topical compositions of the invention can preferably be provided inthe form of a lotion, a thickened lotion, a gel, a cream, a milk, anointment, a powder or a solid tube stick and can be optionally bepackaged as an aerosol and can be provided in the form of a mousse, foamor a spray. The compositions according to the invention can also be inthe form of a suspension or dispersion in solvents or fatty substances,or alternatively in the form of an emulsion or microemulsion (inparticular of O/W or W/O type, O/W/O or W/O/W-type), such as a cream ora milk, a vesicular dispersion, in the form of an ointment, a gel, asolid tube stick or an aerosol mousse. The emulsions can also containanionic, nonionic, cationic or amphoteric surfactants.

The topical application is preferably applied at least once per day,e.g. two or three times a day. Usually it takes at least two days untilthe desired effect is achieved. However, it can take several weeks oreven months until the desired effect is achieved.

According to the invention for preparing the compositions the activeingredients can be used as such or in an encapsulated form, for examplein a liposomal form. Liposomes are preferably formed with lecithins withor without addition of sterols or phytosterols. The encapsulation of theactive ingredients can be alone or together with other activeingredients.

In the composition of the invention, in particular the topicalcompositions of the invention, the compound of formula (I) is containedin an amount of preferably 0.0001 wt.-% to about 50 wt.-%, based on thetotal weight of the composition. More preferably, the compound iscontained in the composition in an amount of about 0.01 wt.-% to about20 wt.-%, more preferably in an amount of about 0.1 wt.-% to about 5wt.-%, in particular in an amount of about 0.2 wt—% to 1 wt.-%, based onthe total amount of the composition.

In case that the (preferably topical) composition of the inventioncontains a further active ingredient, this further active ingredient iscontained in an amount of preferably 0.0001 wt.-% to about 50 wt.-%,based on the total weight of the composition. More preferably, thefurther active ingredient is contained in the composition in an amountof about 0.01 wt.-% to about 20 wt.-%, more preferably in an amount ofabout 0.01 wt.-% to about 1 wt.-%, in particular in an amount of about0.1 wt.-% to 1 wt. %, based on the total amount of the composition.

Regarding the kind of the topical composition and the preparation of thetopical compositions as well as for further suitable additives, it canbe referred to the pertinent literature, e.g. to Novak G. A., Diekosmetischen Präparate—Band 2, Die kosmetischen Präparate—Rezeptur,Rohstoffe, wissenschaftliche Grundlagen (Verlag für Chem. Industrie H.Ziolkowski KG, Augsburg).

It is furthermore possible to provide the compositions of the presentinvention as oral composition, e.g. in the form of pills, tablets,capsules which may contain granules or pellets, as a liquid, oralcomposition or as an additive to foodstuff as is generally known to askilled person. Useful procedures and useful additives for preparing theoral compositions of the present invention are e.g. disclosed in thestandard literature Remington: The Science and Practice of Pharmacy,Lippincot, Williams & Wilking (Editors) 2000, which is included hereinby reference.

As usual additives for oral compositions, in particular for tablets,usual excipients such as micro-crystalline cellulose, sodium citrate,calcium carbonate, disodium or dipotassium phosphate, sodium orpotassium phosphate, glycine, disintegration agents such as starch oralginic acid, binders such as polyvinylpyrolidone, saccharose, gelatinand gum arabicum lubricants such as magnesium stearate, sodium laurylsulfate or talcum can be used. If the compositions are filed intogelatin capsules, usual additives for the preparation of granules arelactose or lactate as well as polyethylene glycols with a high molecularweight. Further additives and excipients as well as additives andexcipients for other oral compositions and for food additives are knownto a skilled person, and it can be referred to the pertinent literaturesuch as “Grundzüge der Lebensmitteltechnik”, Horst Dieter Tscheuschner(Editor), 2. Edition, Hamburg, Beers 1996.

The total content of the active ingredients in the oral compositions ofthe present invention is usually about 1% to 90%, preferably about 10%to 80%, e.g. about 50% or more. The application is such that the desiredeffect occurs and depends on the patient and the desired effect. A usualdaily dosage can be in a range from about 0.1 μg/day to 50 mg/day, e.g.about 20 μg/day to 2 mg/day.

The ability of the compounds and compositions of the present inventionto reduce skin wrinkles can be assessed by profilometric methodsdescribed in “Skin topography measurement by interference fringeprojection: a technical validation”. (Lagarde J M; Rouvrais C; Black D;Diridollou S; Gall Y, Skin research and technology: official journal ofInternational Society for Bioengineering and the Skin (ISBS) [and]International Society for Digital Imaging of Skin (ISDIS) [and]International Society for Skin Imaging (ISSI) (2001 May), 7(2), 112-21or “Direct and non-direct measurement techniques for analysis of skinsurface topography”. Fischer T W; Wigger-Alberti W; Elsner P., Skinpharmacology and applied skin physiology (1999 January-April), 12(1-2),1-11.

The ability of the compounds and compositions of the present inventionto stimulate or protect hair growth can be determined with a mouse modeldescribed for example in WO 9817273. Instead of using Cyclophosphamide(Neostar, Pharmacia) to damage hair follicle Mitomycin, or Methotrexatecan be used. It is also possible to detect hair growth acceleration withnewborn mice. They have a synchronized hair cycle and approximatelyafter 3 weeks all hair follicles go into the telogen phase. Then theanimals are treated and it is evaluated how fast and to what extend thehair is growing Similar tests using in vitro or in vivo setups can alsobe found in J. Invest. Dermato. symposium proceedings 3rd Int. Meetingof Hair Research Societies, 8/1, p. 39-45 (2003).

It also is possible to perform a clinical study including malessuffering from alopecia using the TrichoScan analysis tool described inR. Hoffmann, J. Invest. Dermato. symposium proceedings 3rd Int. Meetingof Hair Research Societies, 8/1, p. 109-115 (2003).

The compositions of the present invention can also be in the form ofinjectable compositions, in particular if the compositions are forpromoting hair growth. The preparation of injectable compositions isknown to a skilled person, and it can be referred to the pertinentliterature, in particular to Remington already cited above.

The compounds of formula (I) can also be present as hydrates orsolvates, and the hydrates and solvates of the active ingredients arealso encompassed by the present invention.

The following examples exemplify the invention, but they should not beconstrued as limiting the invention.

EXAMPLE 1 Synthesis of 4-Phenyl-Butyric Acid3-(2,4-Dihydroxy-3,3-Dimethyl-Butyrylamino)-Propyl Ester

To a solution of D-Panthenol (20.5 g, 100.0 mmol, 1.0 eq.) in dryacetone (400 mL) were added sodium sulphate anhydrous (50.0 g) andp-TsOH monohydrate (1.0 g, 4.0 mmol, 0.04 eq.). The reaction mixture wasstirred at room temperature overnight. p-TsOH monohydrate (500 mg, 2.63mmol, 0.03 eq.) was added again and the reaction mixture stirred at roomtemperature for 6 days until the reaction showed nearly no startingmaterial and no further conversion anymore. Most of the acetone wasremoved under low pressure and the residue was suspended in a saturatedaqueous solution of NaHCO₃ (150 mL) and extracted five times with ethylacetate (200 mL). The organic layers were combined and washed with brine(100 mL) once. The organic layer was dried over Na₂SO₄, filtered and thesolvent was removed under low pressure. The colourless and oily residuewas dried under high-vacuum at room temperature to yield 22.7 g (93%) ofthe product as a white solid. ¹H NMR (CDCl₃) δ=1.01 (s 3H), 1.05 (s,3H), 1.44 (s, 3H), 1.47 (s, 3H), 1.70-1.73 (m, 2H), 3.27-3.71 (m, 9H),4.11 (s, 1H), 6.85 (s, 1H). ¹³C NMR (CDCl₃) δ=18.7, 18.9, 22.1, 29.4,32.4, 33.0, 35.3, 59.1, 71.5, 76.6, 99.1, 171.0.

Panthenolacetonide (15.0 g, 61.2 mmol, 1.0 eq.) was dissolved in DCM(250 mL) and cooled to 0° C. with an ice bath. Pyridine (12.1 g, 153mmol, 2.5 eq.) was first added and then 4-Phenylbutanoylchloride (11.7g, 64.2 mmol, 1.05 eq.) in DCM (70 mL). The reaction was exothermic,therefore the temperature was held in a range of −5° C. to 5° C. Theice-bath was removed after complete addition and the reaction mixturewas allowed to warm up to room temperature overnight. The reaction wasquenched with a saturated aqueous solution of Na₂CO₃ (150 mL) and ethylacetate (200 mL) was added. The layers were separated and the aqueouslayer was extracted twice with of ethyl acetate (150 mL). The combinedorganic layers were washed once with a saturated aqueous solution ofNa₂CO₃ (150 mL) and once with brine (150 mL). The organic layer wasdried over Na₂SO₄, the solvent was removed under low pressure and theresidue dried under high vacuum at room temperature. 24.95 g (104.2%) ofa pale yellow oil were obtained. The crude product was purified by flashchromatography over silica gel with a mixture of tBME/DIPE (1:2, +0.5%triethylamine). 24.1 g (100%) of the acylated Panthenolacetonide as acolourless oil were obtained. ¹H NMR (CDCl₃) δ=0.99 (s, 3H), 1.05 (s,3H), 1.41 (s, 3H), 1.46 (s, 3H), 1.82-1.86 (m, 2H), 1.92-2.00 (m, 2H),2.30-2.35 (q, 2H), 2.61-2.67 (t, 2H), 3.19-3.43 (m, 3H), 3.65-3.69 (d,1H), 4.08-4.15 (m, 3H), 6.71-6.74 (t, 1H), 7.15-7.19 (m, 3H), 7.24-7.31(m, 2H). ¹³C NMR (CDCl₃) δ=18.7, 18.9, 22.1, 22.9, 26.4, 27.0, 28.8,29.5, 32.7, 32.9, 33.2, 33.5, 35.1, 35.6, 49.4, 61.9, 68.2, 71.4, 76.8,99.0, 126.0, 128.3, 128.4, 141.2, 169.7, 173.3. DC (silica gel/tBME/DIPE(1:2, +0.5% triethylamine)) R_(f)=0.41 and 0.25.

The acylated Panthenolacetonide (24.1 g, 61.2 mmol, 1.0 eq.) wassuspended in a mixture of methanol (150 mL) and water (100 mL,deionised). p-TsOH monohydrate (500 mg, 2.63 mmol, 0.04 eq.) was addedand the reaction mixture was stirred overnight at room temperature. Thereaction mixture was quenched with a saturated aqueous solution ofNaHCO₃ (40 mL) and the methanol was distilled of under reduced pressure.The residue, a white suspension, was extracted five times with ethylacetate (200 mL). The organic layers were combined and washed once witha saturated aqueous solution of NaHCO₃ (100 mL) and once with brine (150mL). The organic layer was dried over Na₂SO₄, filtered and the solventwas removed under reduced pressure. The oily residue was dried underhigh vacuum at room temperature overnight. 21.3 g (99%) of pale yellowoil were obtained. The crude product was purified by flashchromatography over silica gel with tBME as solvent. 14.9 g (69%) of4-phenyl-butyric acid 3-(2,4-dihydroxy-3,3-dimethyl-butyrylamino)-propylester as a colourless oil were obtained. ¹H NMR (CDCb₃) δ=0.90 (s, 3H),0.98 (s, 3H), 1.79-1.99 (m, 4H), 2.3-2.36 (t, 2H), 2.61-2.66 (t, 2H),3.23-3.42 (m, 2H), 3.47 (s, 2H), 3.99-4.00 (d, 1H), 4.07-4.13 (m, 3H),4.64-4.65 (d, 1H), 7.15-7.30 (m, 5H). ¹³C NMR (CDCl₃) δ=20.3, 21.2,26.4, 28.7, 33.5, 35.1, 39.3, 60.5, 62.0 71.2 76.7 77.1-77.6 (CDCl₃),126.0, 128.4, 128.5, 141.3, 141.6, 173.7, 173.7. MS (ESI) m/z=352.2(100) [M+H⁺], 374.2 (5) [M+Na⁺], 188 (5) [M-(4-Phenylbutyric acid)+H+],DC (silica gel/tBME) R_(r)=0.25.

EXAMPLE 2 Synthesis of 4-Phenyl-Butyric Acid2-[(Pyridine-3-Carbonyl)Amino]-Ethyl Ester

Ethyl nicotinate (15.1 g, 100.0 mmol, 1.0 eq.) and Ethanolamine (6.1 g,100.0 mmol, 1.0 eq.) were dissolved in toluene (80 mL). The reactionmixture was heated to 80° C. and stirred for 48 h. During the reactionthe mixture changed into a sticky emulsion. The emulsion was cooled downto room temperature and the lower phase became solid. The upper liquidphase was decanted and the orange solid was crystallised twice, firstfrom ethyl acetate and then from acetone. The crystals were dried underhigh vacuum at room temperature to give 7.1 g (42%) of the product as awhite, free flowing powder. The ¹H NMR and the 13C NMR corresponds tothe literature (Ogawa, T.; Hatayama, K.; Maeda, H.; Kita, Y. Chem.Pharm. Bull. 1994, 42 (8) 1579-1589). ¹H NMR (CDCl₃) δ=3.60-3.64 (q,2H), 3.82-3.85 (t, 2H), 4.00 (s, 1H), 7.33-7.39 (m, 2H), 8.10-8.14 (m,1H), 8.64-8.67 (q, 1H), 8.99-9.00 (t, 1H). ¹³C NMR (CDCl₃) δ=42.8, 61.5,123.6, 130.2, 135.5, 147.8, 152.0, 166.4.

N-(2-Hydroxy-ethyl)-nicotinamide (3.3 g, 20.0 mmol, 1.0 eq.) wasdissolved in DCM (100 mL) and pyridine (20 mL). The light yellowsolution was cooled to 2° C. A solution of 4-phenylbutanoylchloride(3.65 g of 20 mmol, 1.0 eq.) in DCM (25 mL) was slowly added. Thereaction mixture was stirred for 1 h at 0° C. The reaction mixture wasevaporated under reduced pressure and the residue was dissolved in water(100 mL) and ethyl acetate (100 mL). The layers were separated and theaqueous phase was extracted with ethyl acetate (75 mL). The combinedorganic layers were washed with a saturated aqueous solution of NaHCO₃(50 mL) and of brine (50 mL). The organic layer was dried over Na₂SO₄,filtrated and evaporated under reduced pressure. The yellow, oilyresidue was dried at high vacuum at room temperature to give 6.2 g(100%) of the product as yellow oil. The crude product was purified byflash chromatography over silica gel with ethyl acetate to yield thepure 4-phenyl-butyric acid 2-[(pyridine-3-carbonyl)amino]-ethyl ester5.6 g (89%) as a light yellow oil. ¹H NMR (CDCl₃) δ=1.87-1.95 (m, 2H),2.29-2.34 (m, 2H), 2.58-2.63 (m, 2H), 3.67-3.72 (m, 2H), 4.25-4.29 (m,2H), 7.11-7.41 (m, 7H), 8.08-8.12 (m, 1H), 8.65-8.67 (q, 1H), 8.99-9.00(d, 1H). ¹³C NMR (CDCl₃) δ=26.3, 33.4, 35.0, 39.6, 62.9, 123.5, 126.0,128.4, 128.4, 130.0, 135.2, 141.1, 148.1, 152.1, 165.8, 173.9. MS (ESI)m/z=313.2 (100) [M+H+]. DC (silica gel/ethyl acetate): R_(F)=0.32.

EXAMPLE 3 Synthesis of 4-Phenyl-butyric acid1,5-dimethyl-1-(4-methyl-cyclohex-3-enyl)-hex-4-enyl ester

To a solution of rac-alpha-Bisabolol (267 mg, 1.2 mmol, 1.2 eq.) intoluene (5 mL), silver cyanide (268 mg, 2 mmol, 2.0 eq.) was added. Thereaction mixture was heated to 80° C. Then 4-phenylbutanoylchloride (182mg, 1 mmol, 1.0 eq.) was added and the reaction mixture was stirredovernight at 80° C. A sample was taken and analyzed by GC-MS. The massof the alpha-Bisabolol was found: (El) m/z=204, 147, 119, 109, 104, 91,69, 41. The reaction mixture containing 4-phenyl-butyric acid1,5-dimethyl-1-(4-methyl-cyclohex-3-enyl)-hex-4-enyl ester can be workedup by standard procedures.

EXAMPLE 4 Synthesis ofN-furan-2-yl-methyl-4-phenyl-N-(9H-purin-6-yl)-butyramide

To a suspension of Kinetin (1.26 g, 5.85 mmol, 1.0 eq.) in dry DMF (25mL) was added triethylamine (651 mg, 6.44 mmol, 1.1 eq.). Then tritylbromide (2.08 g, 6.44 mmol, 1.1 eq.) was added and the mixture wasstirred at room temperature over night. Reaction control by DC(hexane/ethyl acetate 1:1) showed still Kinetin. The reaction mixturewas stirred further 3 hours at 50° C. Reaction control by DC(hexane/ethyl acetate 1:1) showed only small traces of remainingKinetin. The reaction mixture was quenched with a saturated aqueoussolution of NaHCO₃ (30 mL). The yellow solution was extracted threetimes with ethyl acetate (75 mL). The combined organic layers werewashed with a saturated aqueous solution of NaHCO₃ (50 mL) and once withbrine (50 mL). The organic layer was dried over Na₂SO₄, filtered and thesolvent was removed under reduced pressure. The residue was dried inhigh-vacuum at room temperature to yield 3.21 g (120%) of a brownamorphous solid. The crude product was purified by flash-chromatographywith ethyl acetate/hexane 1:2 as eluent. 1.41 g (53%) of a light beigesolid were obtained. —¹H NMR (CDCl₃) δ=4.82-4.83 (d, 2H), 6.29 (s, 2H),6.45-6.49 (t, 1H), 7.14-7.31 (m, 16H), 7.71 (s, 1H), 8.14 (s, 1H). —¹³CNMR (CDCl₃) δ=75.8, 107.5, 110.4, 121.3, 127.9, 128.0, 129.8, 141.4,142.2, 151.8, 152.4, 154.6. —DC (ethyl acetate/hexane 1:2): R_(f)=0.33.

A suspension of furane-2-ylmethyl-(9-trityl-9H-purine-6-yl)-amine (1.00g, 2.186 mmol, 1.0 eq.) in toluene (40 mL) was heated to 65° C. and aclear pale yellow solution was obtained. Then silver cyanide (585 mg,4.371 mmol, 2.0 eq.), triethylamine (266 mg, 2.633 mmol, 1.2 eq.) and4-phenylbutanoyl chloride (439 mg, 2.404 mmol, 1.1 eq.) were added. Thereaction mixture was stirred for 3 hours at 65° C. Reaction control byDC showed still starting material. Another portion of triethylamine (266mg, 2.633 mmol, 1.2 eq.) and 4-phenylbutanoyl chloride (439 mg, 2.404mmol, 1.1 eq.) were added. The reaction mixture was stirred for 1 hourat 70° C. Reaction control by DC showed no more starting material. Thereaction mixture was cooled to room temperature, ethyl acetate (100 mL)was added and the solution was washed with a saturated aqueous solutionof NaHCO₃ (50 mL) and brine (50 mL). The organic layer was dried overNa₂SO₄, the solvent was removed under reduced pressure and the residuewas dried in high vacuum at room temperature to yield 1.93 g (146%) of abrown oil. The crude product was purified by flash-chromatography with amixture of hexane/ethyl acetate 4:1 to give 720 mg (55%) of a paleyellow solid. —¹H NMR (CDCl₃) δ=1.95-2.05 (m, 2H), 2.56-2.63 (m, 4H),5.50 (s, 2H), 6.14-6.19 (m, 2H), 7.06-7.42 (m, 21H), 8.00 (s, 1H), 8.41(s, 1H). —¹³C NMR (CDCl₃) δ=26.9, 35.1, 35.2, 43.6, 76.4, 108.0, 110.2,125.7, 128.1, 128.2, 128.5, 129.7, 140.9, 141.8, 145.0, 151.3, 153.1,154.4, 173.8. —DC (hexane/ethyl acetate 4:1): R_(f)=0.40.

N-furane-2-ylmethyl-4-phenyl-N-(9-trityl-9H-purine-6-yl)-butyramide (650mg, 1.11 mmol) was dissolved in a mixture of DCM with 1% deionised waterand 0.2% TFA (55 mL). The clear pale brown solution was stirred for 2hours at room temperature. Reaction control by DC showed no morestarting material. To the reaction mixture was added ethyl acetate (100mL) and the solution was washed twice with a saturated aqueous solutionof NaHCO₃ solution (50 mL). The combined aqueous layers were extractedtwice with ethyl acetate (50 mL). The combined organic layers werewashed once with brine (75 mL) and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was dried in high vacuumat room temperature to yield 700 mg (175%) of a pale brown solid. Thecrude product was purified by flash-chromatography using hexane/ethylacetate 1:1 to give 260 mg (65%) ofN-furan-2-yl-methyl-4-phenyl-N-(9H-purin-6-yl)-butyramide as acolourless gum. —¹H NMR (MeOH-d₄) δ=1.76-1.86 (m, 2H), 2.37-2.45 (m,4H), 4.78 (s, 2H), 5.23 (s, 2H), 6.00-6.06 (t, 1H), 6.06-6.07 (t, 1H),6.89-7.05 (m, 4H), 7.11-7.12 (d, 1H), 8.31 (s, 1H), 8.63 (s, 1H). —¹³CNMR (MeOH-d₄) δ=28.2, 35.5, 35.9, 44.5, 109.4, 111.2, 126.9, 129.3,129.4, 142.7, 143.4, 146.2, 152.0, 153.0, 175.5. —DC (hexane/ethylacetate 1:1): R_(f)=0.20.

EXAMPLE 5

Anti-aging cream O/W emulsion with 4-Phenyl-Butyric Acid3-(2,4-Dihydroxy-3,3-Dimethyl-Butyrylamino)- Propyl Ester (Compound ofExample 1) Ingredients % (w/w) Glyceryl Myristate 4.00 Cetyl Alcohol2.00 Steareth-2 2.00 Steareth-21 2.00 Isopropyl Myristate 5.00Caprylic/Capric Triglyceride 8.00 BHT 0.05 Dimethicone 2.00Phenoxyethanol & Methylparaben & 0.80 Ethylparaben & Butylparaben &Propylparaben & Isobutylparaben Compound of Example 1 0.50 Water Ad 100Xanthan Gum 0.50 Disodium EDETA 0.10 Propylene Glycol 4.00

EXAMPLE 6

Anti-aging cream O/W emulsion with 4-Phenyl-Butyric Acid2-[(Pyridine-3-Carbonyl)Amino]-Ethyl Ester (Compound of Example 2Ingredients % (w/w) Glyceryl Myristate 4.00 Cetyl Alcohol 2.00Steareth-2 2.00 Steareth-21 2.00 Isopropyl Myristate 5.00Caprylic/Capric Triglyceride 8.00 BHT 0.05 Dimethicone 2.00Phenoxyethanol & Methylparaben & 0.80 Ethylparaben & Butylparaben &Propylparaben & Isobutylparaben Compound of example 2 0.50 Water Ad 100Xanthan Gum 0.50 Disodium EDETA 0.10 Propylene Glycol 4.00

EXAMPLE 7

Anti-aging cream O/W emulsion with 4-Phenyl-butyric acid1,5-dimethyl-1-(4-methyl-cyclohex-3-enyl)- hex-4-enyl ester (Compound ofExample 3) Ingredients % (w/w) Glyceryl Myristate 4.00 Cetyl Alcohol2.00 Steareth-2 2.00 Steareth-21 2.00 Isopropyl Myristate 5.00Caprylic/Capric Triglyceride 8.00 BHT 0.05 Dimethicone 2.00Phenoxyethanol & Methylparaben & 0.80 Ethylparaben & Butylparaben &Propylparaben & Isobutylparaben Compound of example 3 0.50 Water Ad 100Xanthan Gum 0.50 Disodium EDETA 0.10 Propylene Glycol 4.00

1. A compound of the general formula [Ph-(CH₂)_(n)—CO]_(m)—X  (I) wherein Ph is phenyl or substituted phenyl, n is 1 or 3, m is an integer of at least 1, and X is a moiety from a naturally occurring, non-toxic compound carrying at least one hydroxy, sulflhydryl, amino or imino group which moiety is formed by removal of a hydrogen atom from said hydroxyl, sulflhydryl, amino or imino group; except that X is not an amino acid or peptide comprising up to 6 amino acids.
 2. The compound as in claim 1 wherein Ph is phenyl.
 3. The compound as in claim 1 wherein Ph is phenyl substituted by up to three substituents which are selected, independently, from hydroxy, C₁-C₆ alkyl C₂-C₆ alkenyl, C₁-C₆ alkoxy and C₂-C₆ alkenyloxy.
 4. The compound as in claim 1 wherein X is a moiety from a naturally occurring, non-toxic compound carrying at least one hydroxyl group.
 5. The compound as in claim 1 wherein the naturally occurring, non-toxic compound carrying at least one hydroxyl group is selected from fat-soluble vitamin derivatives and analoga thereof, water-soluble vitamins, derivatives or analogues thereof, carbohydrates, α-hydroxy-carboxylic acids, aliphatic alcohols and polyols, aminoalcohols, chromanes and flavones, derivatives and analogues thereof, pyrimidines or purines or metabolites or analogues thereof, terpenes, and catechols;
 6. The compound as in claim 5 wherein the naturally occurring, non-toxic compound carrying at least one hydroxyl group is selected from a fat-soluble vitamin, derivatives and analogues thereof.
 7. The compound as in claim 6 wherein the fat-soluble vitamin or derivative or analogue thereof is selected from a tocopherol, a carotenoid, and vitamin D3 or a hydroxyl derivative thereof.
 8. The compound as in claim 5 wherein the naturally occurring, non-toxic compound carrying at least one hydroxyl group is selected from a water-soluble vitamin, derivatives or analogues thereof.
 9. The compound as in claim 8 wherein the water-soluble vitamin or derivative or analogue thereof is one belonging to the vitamin B group.
 10. The compound as in claim 9 wherein the water-soluble vitamin or derivative or analogue thereof is selected from panthenol, pantothenic acid, pyridoxines, thiamine, riboflavin, nicotinamide, 2-hydroxyethylnicotinamide and folic acid, preferably panthenol, nicotinamide, or 2-hydroxyethylnicotinamide.
 11. The compound of claim 10 which is 4-phenylbutyric acid 2-[(pyridine-3-carbonyl)amino]-ethyl ester.
 12. The compound of claim 10, which is 4-phenylbutyric acid 3-(2,4-dihydroxy-3,3-dimethyl-butyrylamino)-propyl ester.
 13. The compound as in claim 8 wherein the water-soluble vitamin or derivative is ascorbic acid or ascorbic acid phosphate.
 14. The compound as in claim 5 wherein the naturally occurring, non-toxic compound carrying at least one hydroxyl group is selected from chromanes and flavones, derivatives and analogues thereof.
 15. The compound as in claim 14 wherein the chromane, flavone, derivative and analogue thereof is selected from equol, quercetin, delphinidin, silymarin, daidzein, or genistein.
 16. The compound as in claim 5 wherein the naturally occurring, non-toxic compound carrying at least one hydroxyl group is a pyrimidine or purine or metabolite or analogue thereof.
 17. The compound as in claim 16 wherein the pyrimidine or purine or analogue thereof is kinetin or allantoin, preferably kinetin.
 18. The compound of claim 17 which is N-furan-2-yl-methyl-4-phenyl-N-(9H-purin-6-yl)-butyramide.
 19. A compound as in claim 5 wherein the naturally occurring, non-toxic compound carrying at least one hydroxyl group is a terpene.
 20. A compound as in claim 19 wherein the terpene is selected from franesol, bisabolol, phytol and menthol, preferably bisabolol.
 21. The compound of claim 20 which is 4-phenylbutyric acid 1,5-dimethyl-1-(4-methyl-cyclohex-3-enyl)-hex-4-enyl ester.
 22. The compound as in claim 5 wherein the naturally occurring, non-toxic compound carrying at least one hydroxyl group is a catechol.
 23. The compound as in claim 22 wherein the catechol is epigallocatechin gallate.
 24. A topical composition comprising at least one compound as in claim 1 and a cosmetically or pharmaceutically acceptable excipient or diluent.
 25. The composition as in claim 24 wherein the compound of formula (I) is present in a concentration of 0.001 to 50 wt.-%, based on the total weight of the composition.
 26. The composition as in claim 24 wherein the compound of formula (I) is present in a concentration of 0.01 to 1 wt.-%, based on the total weight of the composition.
 27. A method of treatment or prophylaxis of wrinkles or dry skin or sensitive skin or any symptoms caused by negative developments of the physiological homeostasis of healthy skin, promotion of hair growth, protection from hair loss, a thickening of the epidermis, anti-acne, the inhibition of senescence of skin cells, prevention or treatment of photo damage, prevention or treatment of oxidative stress phenomena, prevention or treatment of cellulite, prevention or treatment of pigmentation disorders and/or even the skin tone, prevention and treatment of disturbances in ceramide and lipid synthesis, prevention of excess sebum production, reduction of activities of matrix metallo proteases or other proteases in the skin, treatment and prevention of inflammatory skin conditions including atopic eczema, polymorphic light eruption, psoriasis, vertiligo, prevention and treatment of itchy or irritated skin, which comprises applying an effective amount of composition of claim 24 on the appropriate portions of the skin of the individual in need of such treatment. 